title: Tob1 plays a critical role in the activation of encephalitogenic T cells in CNS autoimmunity.
abstract: Reliable biomarkers corresponding to disease progression or therapeutic responsiveness in multiple sclerosis (MS) have not been yet identified. We previously reported that low expression of the antiproliferative gene TOB1 in CD4⁺ T cells of individuals presenting with an initial central nervous system (CNS) demyelinating event (a clinically isolated syndrome), correlated with high risk for progression to MS. We report that experimental autoimmune encephalomyelitis (EAE) in Tob1⁻/ ⁻ mice was associated with augmented CNS inflammation, increased infiltrating CD4⁺ and CD8⁺ T cell counts, and increased myelin-reactive Th1 and Th17 cells, with reduced numbers of regulatory T cells. Reconstitution of Rag1⁻/ ⁻mice with Tob1⁻/⁻ CD4⁺ T cells recapitulated the aggressive EAE phenotype observed in Tob1⁻/⁻ mice. Furthermore, severe spontaneous EAE was observed when Tob1⁻/⁻ mice were crossed to myelin oligodendrocyte glycoprotein–specific T cell receptor transgenic (2D2) mice. Collectively, our results reveal a critical role for Tob1 in adaptive T cell immune responses that drive development of EAE, thus providing support for the development of Tob1 as a biomarker for demyelinating disease activity.
authors.affiliation: Department of Neurology, University of California, San Francisco, CA 94143, USA.
authors.forename: Ulf
authors.initials: U
authors.lastname: Schulze-Topphoff
authors.forename: Simona
authors.initials: S
authors.lastname: Casazza
authors.forename: Michel
authors.initials: M
authors.lastname: Varrin-Doyer
authors.forename: Kara
authors.initials: K
authors.lastname: Pekarek
authors.forename: Raymond A
authors.initials: RA
authors.lastname: Sobel
authors.forename: Stephen L
authors.initials: SL
authors.lastname: Hauser
authors.forename: Jorge R
authors.initials: JR
authors.lastname: Oksenberg
authors.forename: Scott S
authors.initials: SS
authors.lastname: Zamvil
authors.forename: Sergio E
authors.initials: SE
authors.lastname: Baranzini
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000235:genetics / Q000276:immunology*; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology* / Q000473:pathology; D005260:Female; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008213:Lymphocyte Activation; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000473:pathology
chemical_list: D002352:Carrier Proteins; D047908:Intracellular Signaling Peptides and Proteins; C490903:Tob1 protein, mouse